Mutations of the tumor protein p53 gene, a tumor suppressor, are one of the most frequent genetic alterations observed in cancer. It has been reported that mutations in p53 result in the loss of wild-type p53 activity, and the gain of novel oncogenic properties that promote tumor growth and progression. Recent studies have demonstrated that a number of microRNAs (miRs) are involved in the post-transcriptional regulation of p53. The present study demonstrates that miR-600 is a direct negative regulator of p53 through binding a site in the 3′ untranslated region of p53 mRNA in human colorectal cancer (CRC) cells. Overexpression of miR-600 by lentiviral-mediated transduction decreased endogenous levels of p53 protein and inhibited cell proliferation, migration and invasion in mutant p53-expressing human CRC cell lines (SW480, SW620 and DLD-1) in vitro. In addition, silencing of p53 with small interfering RNA led to a similar phenotype. Furthermore, overexpression of miR-600 or p53 knockdown suppressed the expression of matrix metalloproteinase 9, and promoted the expression of E-cadherin and β-catenin. The results of the current study demonstrate that miR-600 is an important negative regulator of p53, and suggest that targeting mutant p53 using lentiviral-mediated miR-600 overexpression is a promising therapeutic strategy for the treatment of CRCs with p53 mutations.
Although acute myocardial infarction is one of the most common fatal diseases worldwide, the understanding of its underlying pathogenesis continues to develop. Myocardial ischemia/reperfusion (I/R) can restore myocardial oxygen and nutrient supply. However, a large number of studies have demonstrated that recovery of blood perfusion after acute ischemia causes reperfusion injury to the heart. With progress made in the understanding of the underlying mechanisms of myocardial I/R and oxidative stress, a novel area of research that merits greater study has been identified, that of I/R-induced endoplasmic reticulum (ER) stress (ERS). Cardiac I/R can alter the function of the ER, leading to the accumulation of unfolded/misfolded proteins. The resulting ERS then induces the activation of signal transduction pathways, which in turn contribute to the development of I/R injury. The mechanism of I/R injury, and the causal relationship between I/R and ERS are reviewed in the present article.
Creating a microenvironment at the injury site that favors axonal regrowth and remyelinationis pivotal to the success of therapeutic reinnervation. The mature myelin sheath of the peripheral nervous system depends on active participation of Schwann cells to form new cytoskeletal components and tremendous amounts of relevant neurotrophic factors. In this study, we utilized a new biomaterial for growth factor delivery consisting of a biocompatible polycation, poly(ethylene argininylaspartatediglyceride) and heparin. It is capable of binding a variety of growth factors to deliver basic fibroblast growth factor (bFGF) through polyvalent ionic interactions for nerve repair. In vitro assays demonstrated that the bFGF loading efficiency reached 10 μg and this delivery vehicle could control the release of bFGF. In vivo, the coacervate enhanced bFGF bioavailability, which improved both motor and sensory function. It could also acceleratemyelinated fiber regeneration and remyelination and promote Schwann cells proliferation. Furthermore, the neuroprotective effect of bFGF-coacervate in sciatic nerve injury was associated with the alleviation of endoplasmic reticulum stress signal. This heparin-based delivery platform leads to increased bFGF loading efficiency and better controls its release, which will provide an effective strategy for peripheral nerve injury regeneration therapy.
Myocardial infarction is one of the most serious fatal diseases in the world, which is due to acute occlusion of coronary arteries. Grape seed proanthocyanidin extract (GSPE) is an active compound extracted from grape seeds that has anti-oxidative, anti-inflammatory and anti-tumor pharmacological effects. Natural products are cheap, easy to obtain, widely used and effective. It has been used to treat numerous diseases, such as cancer, brain injury and diabetes complications. However, there are limited studies on its role and associated mechanisms in myocardial infarction in mice. This study showed that GSPE treatment in mice significantly reduced cardiac dysfunction and improved the pathological changes due to MI injury. In vitro, GSPE inhibited the apoptosis of H9C2 cells after hypoxia culture, resulting in the expression of Bax decreased and the expression of Bcl-2 increased. The high expression of p-PI3K and p-AKT was detected in MI model in vivo and in vitro. The use of the specific PI3K/AKT pathway inhibitor LY294002 regressed the cardio-protection of GSPE. Our results showed that GSPE could improve the cardiac dysfunction and remodeling induced by MI and inhibit cardiomyocytes apoptosis in hypoxic conditions through the PI3K/AKT signaling pathway.
Transforming growth factor β‐activated protein kinase 1 (TAK1) involves in various biological responses and is a key regulator of cell death. However, the role of TAK1 on acute myocardial ischaemia/reperfusion (MI/R) injury is unknown. We observed that TAK1 activation increased significantly after MI/R and hypoxia/reoxygenation (H/R), and we hypothesized that TAK1 has an important role in MI/R injury. Mice (TAK1 inhibiting by 5Z‐7‐oxozeaenol or silencing by AAV9 vector) were exposed to MI/R injury. Primary cardiomyocytes (TAK1 silencing by siRNA; and overexpressing TAK1 by adenovirus vector) were used to induce H/R injury model in vitro. Inhibition of TAK1 significantly decreased MI/R‐induced myocardial infarction area, reduced cell death and improved cardiac function. Mechanistically, TAK1 silencing suppressed MI/R‐induced myocardial oxidative stress and attenuated endoplasmic reticulum (ER) stress both in vitro and in vivo. In addition, the inhibition of ROS by NAC partially reversed the damage of TAK1 in vitro. Our study presents the first direct evidence that inhibition of TAK1 mitigated MI/R injury, and TAK1 mediated ROS/ER stress/apoptosis signal pathway is important for the pathogenesis of MI/R injury.
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